Long-Term Experience with Radiofrequency-Induced Hyperthermia Combined with Intravesical Chemotherapy for Non-Muscle Invasive Bladder Cancer.

BACKGROUND: The recurrence rate of non-muscle invasive bladder cancer (NMIBC) is high, despite intravesical treatments. Importantly, patients are frequently unfit or unwilling to undergo a recommended radical cystectomy when standard intravesical treatments fail, due to the substantial risk of morbidity and mortality. For these patients, radiofrequency-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We aim to determine treatment outcomes and assess the effect of (ablative) dose. METHODS: 299 intensively pretreated patients treated with RF-CHT were included in safety analysis. Of these, 274 patients who fulfilled induction treatments were included in efficacy analysis. Six-month complete response (CR) and durable response were reported for (concomitant) carcinoma in situ (CIS) patients and recurrence-free survival (RFS) for papillary patients. RESULTS: For CIS, six-month CR-rate was 56.0%; and durable response rates were 79.7%, 66.5%, and 40.3% at one-, two- and five-year, respectively. RFS rates for papillary patients were 77.9%, 57.5%, and 37.2%, respectively. Patients treated with ablative dose are less likely to develop recurrence (adjusted Hazard Ratio 0.54, p = 0.01), compared to adjuvant dose. CONCLUSIONS: RF-CHT is effective in NMIBC patients in whom standard intravesical treatments have failed and should be considered in patients who are unwilling or unfit to undergo radical cystectomy. Patients with CIS or residual papillary tumor at baseline benefit from ablative dose.

Apaziquone for Nonmuscle Invasive Bladder Cancer: Where Are We Now?

Apaziquone is an interesting drug for intravesical use in patients with nonmuscle invasive bladder cancer; however, more research is needed to prove its actual benefit. Although the apaziquone trials demonstrate the potential of this new drug, the singular phase 3 trials did not reach their primary endpoint. To date, no new trials are recruiting, so the development of apaziquone seems to have stopped.

[Chemohyperthermia using MMC in non-muscle-invasive bladder cancer: Current status and future perspectives.] / Quimiohipertermia con MMC en el cáncer de vejiga no músculo invasivo: estado actual y perspectivas futuras.

In an effort to decrease recurrence and progression rates in non-muscle-invasive bladder cancer (NMIBC), transurethral resection of a bladder tumor is followed by intravesical instillations using Mitomycin-C (MMC) and Bacillus Calmette-Guérin (BCG). In spite of these adjuvant treatment modalities, recurrence and progression rates remain high. Because of these limitations of current standard therapy and the shortage of BCG, there is a search for alternative forms of treatment in NMIBC. Intravesical MMC combined with hyperthermia, especially RF-induced QHT being most extensively investigated in the past 20 years, is one of these alternatives for intermediate- and high-risk NMIBC. There are several different techniques and devices to create hyperthermia of the bladder wall raising temperatures up to 40.5-44.0 ℴ C. Hyperthermia can be the result of ultrasound waves, direct thermal conduction, or electromagnetic fields. An overview of hyperthermia systems concerning their technical aspects, treatment outcomes and adverse events (AE's) will be described in this review. In patients failing standard treatment who are not fit or unwilling to undergo surgery, RF-induced QHT should be considered. Besides QHT, there are more forms of treatment currently being investigated in NMIBC like EMDA and neoadjuvant intravesical chemotherapy, these require more clinical trials to determine patient selection and efficiency.

Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue.

INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette-Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation. PATIENTS AND METHODS: Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography. RESULTS: Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group. CONCLUSION: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.

Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer.

BACKGROUND: Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. OBJECTIVE: To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. RESULTS AND LIMITATIONS: The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. CONCLUSIONS: CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. PATIENT SUMMARY: Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy.

Management of low-risk and intermediate-risk non-muscle-invasive bladder carcinoma.

Non-muscle-invasive bladder cancer is a highly recurrent disease. The health care costs for non-muscle-invasive bladder cancer are a major burden for society. Bladder cancer treatment starts with a presumed complete transurethral resection of a bladder tumor. Despite international guidelines for perioperative and/or adjuvant intravesical instillation therapy in non-muscle-invasive bladder cancer, adequate worldwide application is lacking. In patients who do get adjuvant intravesical instillations, recurrences are still frequent. New therapies in non-muscle-invasive bladder cancer are unsatisfactory and still experimental.

Pharmacokinetic, Pharmacodynamic, and Activity Evaluation of TMX-101 in a Multicenter Phase 1 Study in Patients With Papillary Non-Muscle-Invasive Bladder Cancer.

INTRODUCTION/BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. PATIENTS AND METHODS: A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. RESULTS: The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. CONCLUSION: Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer.

PURPOSE: Nonmuscle invasive bladder cancer is characterized by a high recurrence rate. New adjuvant treatments are needed to decrease this high number of recurrences. We present the results of more than 10 years of experience with chemohyperthermia in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Using standardized medical record forms we prospectively collected patient and tumor characteristics of patients treated with chemohyperthermia between 2002 and 2013. Median followup was 75.6 months. Recurrence-free survival was the primary objective. The secondary objective was to observe recurrence-free survival differences in 1) the epirubicin group vs the mitomycin group and 2) the highly recurrent (greater than 2 recurrences in 24 months) nonmuscle invasive bladder cancer group vs the other groups. RESULTS: A total of 160 patients with nonmuscle invasive bladder cancer were included in study, including 20 (13%) treated with epirubicin and 129 (81%) previously treated with bacillus Calmette-Guérin. One and 2-year recurrence-free survival was 60% and 47%, respectively. Muscle invasive progression was seen in 4% of cases. Two-year recurrence-free survival in the epirubicin and mitomycin groups was 55% and 46%, respectively (p = 0.30). The highly recurrent nonmuscle invasive bladder cancer group had significant decreased recurrence-free survival compared to other groups (p <0.01). Patients treated with 2 or fewer vs greater than 2 transurethral bladder tumor resections before chemohyperthermia had higher recurrence-free survival (p = 0.01). On multivariable analysis the highly recurrent cancer criteria remained independently associated with decreased recurrence-free survival (HR 2.40, 95% CI 1.30-4.43, p = 0.01). CONCLUSIONS: Chemohyperthermia is an effective approach to nonmuscle invasive bladder cancer for which standard intravesical treatments fail. Patients with highly recurrent disease before chemohyperthermia have lower recurrence-free survival. Furthermore, recurrence-free survival appears to improve with earlier chemohyperthermia. No significant differences were observed between the 2 chemotherapy agents.

Radical cystectomy in a Dutch University hospital: long-term outcomes and prognostic factors in a homogeneous surgery-only series.

BACKGROUND: The aim of this study was to present survival outcomes and identify prognostic factors in patients undergoing radical cystectomy (RC) for urothelial bladder cancer (UBC) in a homogeneous surgery-only series. PATIENTS AND METHODS: Patients who underwent RC for UBC with intent-to-cure between January 1998 and December 2010 without neoadjuvant or adjuvant treatment were included in this retrospective study. Clinical and histopathologic data were collected and institutional review board approval was obtained. Outcomes of interest were 30-day mortality (30dM), RFS, and OS. Univariable and multivariable analysis were performed. Median follow-up was 9.1 years. RESULTS: Two hundred forty-five patients were included with a median age of 65 years (range, 34-92 years). 30dM rate was in 5 out of 245 patients (2.0%) and 5-year RFS and OS rates were 67% and 58%, respectively. A total of 223 patients (91%) underwent lymph node (LN) dissection. Median number of removed and positive LNs were 9 and 1.5, respectively. Variables independently associated with decreased OS and RFS were tumor stage and LN status. In addition, positive soft tissue surgical margin (STSM) status was independently associated with decreased OS. In LN-positive patients, presence of extranodal extension (ENE) was associated with decreased RFS (39.7% vs. 7.3%; P = .005). CONCLUSION: Radical cystectomy for UBC was associated with low perioperative mortality rate and provided 5-year disease control in approximately two-thirds of patients. Independent prognostic factors included tumor stage, LN status (RFS and OS), and STSM status (OS). Presence of ENE in LN-positive patients was univariably associated with decreased RFS and OS.

Expert review: an update in current and developing intravesical therapies for non-muscle-invasive bladder cancer.

Non-muscle-invasive bladder cancer is a highly prevalent disease and recurrences, after initial therapy, are common. Consequently, the healthcare costs for non-muscle-invasive bladder cancer are high. Despite a primary adequate response to adjuvant intravesical treatment, many patients suffer from recurrences, and some even from progression. To date, cystectomy remains the only option for those non-responding patients with high risk of recurrence and progression. Mainly because outcome after progression, in this group, is poor. Therefore, new intravesical therapies are needed. Moreover, new accurate and individual parameters, to distinguish responder from non-responders, will provide additional benefit in clinical decision-making. In this review, current diagnostics and therapies will be discussed. In addition, we will elucidate developing therapies in non-muscle-invasive bladder cancer.